Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

• Published in: European journal of immunology 2007-05, Vol.37 (5), p.1323-1333
• Main Authors: Wooldridge, Linda, Lissina, Anna, Vernazza, Jonathan, Gostick, Emma, Laugel, Bruno, Hutchinson, Sarah L., Mirza, Fareed, Dunbar, P. Rod, Boulter, Jonathan M., Glick, Meir, Cerundolo, Vincenzo, van den Berg, Hugo A., Price, David A., Sewell, Andrew K.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Antigen Presentation - genetics; Antigen Presentation - immunology; CD8; CD8 Antigens - chemistry; CD8 Antigens - immunology; CD8 Antigens - metabolism; Cytotoxic T cells; Epitopes, T-Lymphocyte - immunology; HLA-A Antigens - genetics; HLA-A Antigens - immunology; HLA-A Antigens - metabolism; HLA-A2 Antigen; Humans; Immunomodulation; Lymphocyte Activation - immunology; MHC class I; Molecular Sequence Data; Mutation; Protein Structure, Quaternary; Receptors, Antigen, T-Cell - immunology; Surface Plasmon Resonance; T cell activation; T-Lymphocytes, Cytotoxic - immunology; Transfection; Tumor immunity
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.200636765

CD8+ cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide‐MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the α2 domain of human leukocyte antigen (HLA)‐A*0201 that enhances CD8 binding by ∼50% without altering TCR/pMHCI interactions. Soluble and cell surface‐expressed forms of Q115E HLA‐A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8‐enhanced antigens induce greater CD3 ζ chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.